The long-term goals of our proposed studies are to understand the role of the neuropeptide calcitonin gene-related peptide (CGRP) in promoting neuron-glia interactions in the trigeminal system that facilitate development of persistent pain, and test novel therapeutic strategies to treat temporomandibular joint disorders (TMJD). As reported by NIDCR, temporomandibular disorders (TMD) that involve inflammation and pain in the joint or muscles of mastication, is the most common chronic orofacial pain and is the second most common chronic pain condition. Increased neuron-glia interactions and release of inflammatory cytokines in the trigeminal ganglia and spinal trigeminal nucleus (STN) are implicated in the underlying pathology of TMD by promoting sensitization of primary and secondary nociceptive neurons. Based on results from our preliminary studies, we hypothesize that CGRP plays an important role in initiating and maintaining sensitization of trigeminal nociceptive neurons implicated in TMD. To test our hypothesis, in Aim 1 we will investigate the temporal effects of elevated CGRP levels on cytokine expression in the STN and correlate cellular changes to nocifensive behavioral responses to heat and mechanical stimulation of trigeminal nociceptors. In Aim 2, the role of CGRP in promoting trigeminal sensitization will be studied in an established model of TMJD pathology that involves injection of complete Freund's adjuvant (CFA) into the temporomandibular joint (TMJ) capsule. Specifically, effects of intrathecal injection of the CGRP receptor antagonist CGRP8-37 on CFA- induced changes in cytokines and behavioral responses will be determined. Finally, in Aim 3, we will investigate the role of CGRP and cytokines in the development of trigeminal sensitization in a novel mechanically-induced model of TMJD. We predict that results from our studies will support an important role of CGRP in promoting and maintaining a sensitized state of trigeminal nociceptors, and therefore antagonism of CGRP receptors is a potential therapeutic target for TMJD.